A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988), demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313,277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. The end product compounds, including Compound J which is shown in Example 29 below, that can be made from the novel intermediates and processes of this invention are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993.
Previously, the synthesis of Compound J and related compounds was accomplished via a 12-step procedure. This procedure is illustrated in EPO 541,168. In prior methods, the HIV protease inhibitor J was prepared by coupling of the epoxide intermediate 2 with the Boc-protected piperazine carboxamide 4 to afford the Boc-protected coupled intermediate 5. Deblocking of 5 then afforded a penultimate Compound 6 which was subjected to picolylation to afford J. The disadvantage with this route is that three chemical steps are necessary to convert the epoxide 2 to J. Thus, after deblocking, a separate picolylation step is necessary to effect conversion to J. ##STR2##
Since the more reactive 4-position of the piperazine carboxamide must be protected prior to coupling, the most efficient blocking method for the chiral 2-piperazine-t-butylcarboxamide would be the incorporation of the 3-picolyl moiety at this point, i.e., piperazine 1. However, it was unexpected that the reaction of piperazine 1 with epoxide 2 would be efficient, since piperazine 1 contains three basic amine functions capable of attacking the epoxide 2. The Boc-protected piperazine 4, however, contains only one basic amine function, and thus it was expected that the coupling of 2 and 4 would be straightforward.
More recently, a convenient process to prepare the HIV protease inhibitor J from the 4-picolyl piperazine carboxamide 1via a two-step procedure has been discovered. The piperazine 1 is condensed with epoxide 2 to afford the coupled product 3. Removal of the acetonide protecting group of 3 directly affords the HIV-1 protease inhibitor J. ##STR3##
The synthesis of the chiral piperazine-2-carboxamide intermediates is currently achieved in a stepwise manner from an aromatic 2-pyrazine carboxylic acid precursor. First, the t-butylcarboxamide is prepared from commercially available pyrazine-2-carboxylic acid by activation as the acid chloride followed by reaction with t-butylamine to form pyrazine-2-t-butylcarboxamide. Subsequently, the pyrazine ring is reduced through a hydrogenation to afford racemic piperazine t-butylcarboxamide. If resolution is required, it can be effected at this point via optically active acids to obtain optically enriched material. In the case of the Compound J intermediate, the resolution is carried out at this stage with either (S)-10-camphorsulfonic acid or L-pyroglutamic acid to afford the desired (S)-antipode. A protection to differentiate N.sub.1 and N.sub.4 of the piperazine then affords predominantly the desired 4-protected piperazine derivative. In the case of the Compound J intermediate, the protection is carded out with di-t-butyldicarbonate and affords about a 9:1 ratio of N.sub.4 -BOC protected product and 1,4-bis-protected product. If the reaction is carded out with 3-picolyl chloride to introduce the 3-picolyl group at the 4-piperazine position in Compound J, however, very low selectivities result (4:1 mono/bis alkylation), which affords a mixture that cannot be purified by crystallization. This method for preparing the piperazine-2-t-butylcarboxamide intermediates require several distinct steps and is labor intensive and complicated from a factory design standpoint. Thus, a need remains for a more efficient and simplified process for making the key piperazine-2-carboxamide intermediates. ##STR4##
The four component Ugi condensation [Ivar Ugi, et al., in Comprehensive Organic Synthesis, Vol. 2, page 1083 (B. M. Trost, ed. and Strecker condensation [D. T. Mowry, Chem. Rev., 42; 236, (1948)] are well-known methods for the preparation of amino acids and peptide derivatives. The characteristic feature of the Ugi reaction is the .alpha.-addition of an isocyanide and the anion X of a suitable acid HX to an iminium ion (40), followed by a spontaneous rearrangement of the .alpha.-adduct (41) into a stable .alpha.-aminocarboxamide derivative (42). ##STR5##
Thus, the product results from four distinct reactants, namely (4), (5), (43) and HX, through a condensation reaction. Therefore, such an Ugi reaction was initially called the four-component condensation (4CC). While in principle a very powerful method, the Ugi reaction was unknown for the preparation of piperazine carboxamides.
The Strecker synthesis of amino acids has proven extremely useful to synthetic organic chemists since its discovery in 1850. Strecker treated acetaldehyde ammonia with hydrogen cyanide and hydrolyzed the product to obtain alanine. [D. T. Mowry, Chem. Rev., 42, 236 (1948)] ##STR6##
In its most general form, the Ritter reaction [L. I. Krimen and D. J. Cota, Organic Reactions, Vol. 17, 213 (1969)] involved the nucleophilic addition of a nitrile to a carbonium ion in the presence of sulfuric acid. ##STR7## Subsequent dilution with water yields the amide. ##STR8##
While the Strecker synthesis is known to afford 2-amino acids after hydrolysis of the corresponding 2-arninonitriles, the analogous Ritter reaction of the aminonitriles to directly afford the 2-aminocarboxamide derivatives is not well known. Moreover, this transformation is unexpected since 2-aminonitriles have been reported to undergo undesired conversions to the 2-hydroxy-carboxamide products in the Ritter reaction [D. Giraud-Clenet and J. Anatol, Compt. Rend., 262, 244 (1966)].
It has now been found that the Ugi reaction, as well as the Strecker and Ritter reactions, can be employed in the synthesis of the piperazine 2-carboxamide intermediates. Thus, the present invention provides improved methods for forming the key intermediates with increased simplicity and efficiency, resulting in savings in capital and labor. Additionally, the improved methods of the present invention result in decreased formation of waste by-products than in previously known methods for forming the key piperazine-2-carboxamide intermediates.